Regulation of the tonsil cytokine milieu favors HIV susceptibility

Mucosal associated lymphoid tissues are major targets of HIV during early infection and disease progression but can also provide a viral safe haven during highly active antiretroviral therapy. Among these tissues, the tonsils remain enigmatic regarding their status as primary and/or secondary sites of retroviral infection. To dissect the mechanisms underlying susceptibility to HIV in this compartment, isolated tonsil cells were studied for phenotypic and functional characteristics, which may account for their permissiveness to infection. For this, tonsil cells and PBMC were infected in parallel with HIV, and viral replication was monitored by p24 ELISA. Our results demonstrate that unstimulated tonsil cells were more readily infected than PBMC with HIV. Phenotypic characterization of the tonsil cells revealed heterogeneous lymphoid populations but with increased expression of early activation markers and the viral co-receptor CXCR4, relative to PBMC, all of which may contribute to viral susceptibility. Furthermore, the cytokine microenvironment appeared to be key in facilitating HIV infection and tonsil-secreted products enhanced HIV infection in PBMC. Of the cytokines detected in the tonsil supernatants, TH2 cytokines, particularly IL-4, promoted HIV infection and replication. Interestingly, this TH2 profile appeared to dominate, even in the presence of the TH1 cytokine IFN gamma and the antiviral factor IFN alpha, likely due to the enhanced expression of suppressor of cytokine signaling (SOCS) proteins, which may disengage IFN signaling. These and other local environmental factors may render tonsil cells increasingly susceptible to HIV infection. J. Leukoc. Biol. 80: 1145-1155; 2006.